New Multiple Sclerosis Diagnostic Criteria CLINICAL ATTACKS OBJECTIVEADDITIONAL REQUIREMENTS 2 or more None; clinical evidence will suffice 2 or more1Dissemination in space by MRI, or, positive CSF and 2 or more MRI lesions c/w MS or second clinical attack at a different site 12 or moreDissemination in time by second MRI or, second clinical attack 11Dissemination in space by MRI, OR positive CSF and 2 or more MRI lesions AND Dissemination in time by by MRI or second clinical attack 01Positive CSF AND dissemination in space by MRI evidence of 9 or more T2 lesions, Or 2 or more cord lesions, or 4-8 brain lesions and 1 cord lesion, or positive VEP with 4-8 MRI lesions or, positive VEP, 1 cord lesion and <4 brain lesions AND dissemination in time by MRI

Axons are Transected in MS Plaques Trapp BD, et al. N Engl J Med. 1998;338: SMI-32 (non-phosphorylated neurofilament) -demyelinated axons and swellings MBP intact axons

Natural History Of MS Clinical and MRI Measures Measures of brain volume Relapses and impairment Time Hartung HP et al. The Lancet 2002;360: MRI Total T2 Lesion Area MRI activity RelapsingPreclinical Progressive

Time from onset of MS (years) Percent of patients Actuarial analysis of disability: percentage of patients not having reached DSS 6: difference between the groups significant (P<0.0001) Early Relapses Affect Long-term Disability Low (0-1 attacks in 2 years) Intermediate (2-4 attacks in 2 years) High (> 5 in 2 years) Weinshenker BG, et al. Brain. 1989;112:1422.

Presence of MRI Lesions Predict Development of MS 16% No lesions* 37% 1-2 lesions* 51% > 3 lesions* ONTT: Optic Neuritis Treatment Trial *Number of lesions present at baseline The exact relationship between MRI findings and the clinical status of patients is unknown Arch Neurol 1993 Aug;50(8):841-6

PRISMS 4 Trial: Transient Effect of NAbs With Rebif 44 mcg tiw SC on Relapse Counts? Prestudy 0-6m 6-12m 12-18m18-24m24-30m30-36m36-42m42-48m # of Relapses Average years 1-4: NAb+ vs NAb- p = NAb + (n=35) NAb − (n=147) PRISMS Study Group. Neurology. 2001;56:1628–1636. The clinical utility of measuring NAb in an individual on IFN-  therapy is uncertain

PRISMS Trial Conclusions Rebif efficacy is sustained over 4 years as measured by: –MRI –Relapses –Disability 44 mcg TIW yields greater efficacy than 22 mcg TIW Patients treated at a high dose early have better outcomes With respect to NAbs, treatment decisions are best made on clinical grounds –By year 4: 7/8 patients are NAb-free Side effects are generally mild and manageable PRISMS Study Group. Neurology. 2001;56:1628–1636.

Summary Efficacy at Week 24 and Week 48 Week 24 Week 48 p-value Relative improvement p-valueRelative improvement Odds Ratio - relapsing % % Hazard ratio, time to relapse % % Relapse rate % % CU active < % T2 lesions < % < % T2 active scans < % < % T2 inactive patients < % < % Neurology. 2002;59: The exact relationship between MRI findings and the clinical status of patients is unknown Rebif vs. Avonex

Natural History Of MS Clinical and MRI Measures Measures of brain volume Relapses and impairment Time Hartung HP et al. The Lancet 2002;360: MRI Total T2 Lesion Area MRI activity RelapsingPreclinical Progressive

PRISMS Trial Conclusions Rebif efficacy is sustained over 4 years as measured by: –MRI –Relapses –Disability 44 mcg TIW yields greater efficacy than 22 mcg TIW Patients treated at a high dose early have better outcomes With respect to NAbs, treatment decisions are best made on clinical grounds –By year 4: 7/8 patients are NAb-free Side effects are generally mild and manageable PRISMS Study Group. Neurology. 2001;56:1628–1636.

EVIDENCE 48 Week Trial: Conclusions Treatment regimen (dose and frequency) has significant and sustained impact on efficacy of IFN  -1a in RRMS at 48 weeks The positive treatment effects seen with Rebif 44  g tiw SC vs. Avonex 30 mcg qw IM at 24 weeks were sustained up to 48 weeks –Proportion of relapse-free patients –MRI activity Efficacy was not achieved at the expense of safety –Despite differences in adverse events, discontinuation rate for adverse events was comparable (Avonex- 4.2%, Rebif – 4.7%) –NAb status had no effect on relapse rate at 48 weeks The exact relationship between MRI findings and the clinical status of patients is unknown. The clinical utility of measuring NAbs in an individual on The clinical utility of measuring NAbs in an individual on IFN  in uncertain. Neurology. 2002;59:

PULSED METHYLPREDNISOLONE Characteristics Pulsed MP, n=39 Control, n=42 P Value Sex, M/F, n (%) 12 (30)/27 (69) 14(33)/28(66)NS RR, Av (SD) 0.6 (0.7) 0.6 (0.3) NS EDSS, av/(SD) 1.7 (1.4) (2.0) 3.0 <.0001 T2, mL, av (SD) 21.4 (25.4)/ (36.4)/1NS T1,mL, av, (SD) 2.7(3.7)/06.7(5.3)/0<.0001 Brain vol mL, (SD) 1,257.4 (64.3) 1,188.9 (139.9) 0.003

Real Power. Real Performance. 31 Evaluating Efficacy—MRI MRI Measures and Meanings Gd-enhanced T1-weighted lesions indicate 24 —Leakage of the BBB —Acute inflammation *Quality of life as measured by sexual dysfunction, overall mental health, and limitations due to physical and emotional dysfunction. Clinical Correlations DisabilityRelapsesQOL*FatigueCognition Weak 24 Moderate 24,25 No 26 No 27 No published reports

Real Power. Real Performance. 32 Evaluating Efficacy—MRI MRI Measures and Meanings T2-weighted lesions indicate 24 —Edema —Moderate demyelination —Gliosis —Axonal loss *Quality of life as measured by sexual dysfunction, overall mental health, and limitations due to physical and emotional dysfunction. Clinical Correlation DisabilityRelapsesQOL*FatigueCognition Weak 24 No 28 Moderate 26 No 29 No 30,31

Real Power. Real Performance. 33 Evaluating Efficacy—MRI MRI Measures and Meanings Black hole lesions (or T1 hypointense lesions) indicate 24,30 —Significant demyelination —Severe tissue damage —Gliosis —Axonal loss Acute vs Chronic T1 Lesions T1-weighted lesion persists over 6-month period defined as a chronic T1 lesion, or black hole Clinical Correlation DisabilityRelapsesQOL*FatigueCognition Strong 32 No 33 Strong 26 No published reports Strong 34

Real Power. Real Performance. 34 Considerations in Long-term Treatment COPAXONE ® : Long-term Relapse Rate Reduction Over the long term (2 years), studies demonstrate a reduction in relapses —29% reduction in relapse rate vs placebo at 2 years in first pivotal trial 1 COPAXONE ® 1.19 vs placebo 1.68 (P=0.055) —75% reduction in relapse rate vs placebo at 2 years in second pivotal trial 2 COPAXONE ® 0.60 vs placebo 2.40 (P=0.005) n=50; 25 COPAXONE ®, 25 placebo Double-blind, randomized, placebo-controlled, multicenter study of glatiramer acetate in relapsing-remitting multiple sclerosis patients (n=251; 125 COPAXONE ®, 126 placebo).

Real Power. Real Performance. 35 Considerations in Long-term Treatment IFNs and Neutralizing Antibodies (NAbs) NAbs may compromise efficacy* Higher relapse rates More Gd-enhancing lesions 36 More T2 active lesions 37 More BOD † accumulation 37 *Based on a comparison of NAb+ vs NAb- patients. † BOD=Burden of disease, defined as the summed cross-sectional area of lesions in T2 scans, analyzed as a percent change from baseline.

Real Power. Real Performance. 36 Considerations in Long-term Treatment IFNs and Neutralizing Antibodies (NAbs) Long-term Effects NAbs in patients (n=167) administered IFN  -44  g 3x/wk compared with NAb- patients included 37 62% increase in relapse rate at years 3 and 4 (P=0.002) 366% increase in T2 active lesions over 4 years (P<0.001) 26% relative increase in BOD* over 4 years (P<0.001) COPAXONE ® IS NOT ASSOCIATED WITH NAbs IN CLINICAL TRIALS 39 *BOD=Burden of disease, defined as the summed cross-sectional area of lesions in T2 scans, analyzed as a percent change from baseline.

Real Power. Real Performance. 37 Considerations in Long-term Treatment COPAXONE ® : Tolerability COPAXONE ® is not associated with the following 14 : Well tolerated over 8 years 1-3 COPAXONE ® is indicated for the reduction of relapses in relapsing-remitting multiple sclerosis. Most common adverse effects in controlled trials were injection site reactions, vasodilatation, chest pain, asthenia, infection, pain, nausea, arthralgia, anxiety, and hypertonia. About 10% of patients experienced an immediate postinjection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and urticaria). The symptoms were transient and self-limited, and did not require specific treatment. Transient chest pain was noted in 21% of COPAXONE  patients (vs 11% placebo); no long-term sequelae.

Real Power. Real Performance. 38 In Conclusion COPAXONE ® : Summary Benefits For the Short Term Early reduction in both Gd enhancement and relapses 1,2,20 Favorable tolerability profile that allows patients to stay with therapy Benefits For the Long Term Long-term reduction in relapses demonstrated in pivotal studies at 2 years 1,2 No evidence of NAbs from clinical trials that may interfere with efficacy 39 Long-term safety of COPAXONE ® demonstrated over 8 years 1-3 Available in a Pre-Filled Syringe for increased patient convenience

Indication Now approved for use in worsening MS: Now approved for use in worsening MS: NOVANTRONE ® is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary progressive, progressive relapsing, and worsening relapsing-remitting MS. NOVANTRONE is not indicated for primary progressive MS. Before prescribing NOVANTRONE, please review important treatment considerations (included in this presentation) and full prescribing information available at or by calling IMMUNEX Before prescribing NOVANTRONE, please review important treatment considerations (included in this presentation) and full prescribing information available at or by calling IMMUNEX

Unfavorable Prognostic Factors High MRI lesion burden at first episode High MRI lesion burden at first episode Moderate-to-severe disability at 5 years Moderate-to-severe disability at 5 years Progressive clinical course from onset Progressive clinical course from onset Male gender Male gender Late onset (age >40 years) Late onset (age >40 years) Two or more relapses in first year Two or more relapses in first year

The Burden of Worsening MS Half of patients with relapsing-remitting MS convert to secondary progressive MS within 10 years of onset Half of patients with relapsing-remitting MS convert to secondary progressive MS within 10 years of onset Within 15 years of diagnosis, about 50% of patients with secondary progressive MS require walking aids and 10% are wheelchair-bound Within 15 years of diagnosis, about 50% of patients with secondary progressive MS require walking aids and 10% are wheelchair-bound

NOVANTRONE ® Efficacy at 2 Years: Primary Efficacy Variables NR=not reached within 24 months. p-value NOVANTRONE NOVANTRONE Placebo 12 mg/m 2 12 mg/m 2 (n=64) (n=60)vs Placebo Multivariate primary efficacy criterion< EDSS change (mean) AI change (mean) Mean no. of treated relapses Time to first treated relapse (median months) 14.2 NR SNS change (mean)

Conclusions: Clinical Efficacy NOVANTRONE ® significantly reduced neurologic disability Significantly reduced EDSS progression Significantly reduced EDSS progression 61% reduction in deterioration in Ambulatory Index 61% reduction in deterioration in Ambulatory Index NOVANTRONE significantly reduced relapse rates Prolonged time to first treated relapse Prolonged time to first treated relapse 67% reduction in the number of treated relapses 67% reduction in the number of treated relapses

MSFC IN MTX+IFN1A Methotrexate and Betainterferon stabilize disease Methotrexate and Betainterferon stabilize disease

Azathioprine and Betainterferon are better together than alone